CN114831940A - Medicine carrying system for carrying anti-cancer medicine and preparation method and application thereof - Google Patents

Medicine carrying system for carrying anti-cancer medicine and preparation method and application thereof Download PDF

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CN114831940A
CN114831940A CN202210532989.5A CN202210532989A CN114831940A CN 114831940 A CN114831940 A CN 114831940A CN 202210532989 A CN202210532989 A CN 202210532989A CN 114831940 A CN114831940 A CN 114831940A
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liposomes
loaded
drug
liposome
anticancer drug
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CN114831940B (en
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陈忠平
黄旭
孙佳佳
刘雪蒙
翁凌燕
朱俐
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Nantong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to the technical field of nano medicaments, and discloses a medicament carrying system for carrying an anticancer medicament, and a preparation method and application thereof. The preparation method comprises the following steps: dissolving 1, 2-dioleoyl-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol, 1, 2-dioleoyl-sn-glycerol-3-phosphate or 1, 2-dioleoyl-3- (dimethylamino) propane and the anticancer drug in dichloromethane, hydrating a layer of phospholipid film obtained by rotary evaporation with triple-distilled water, and dialyzing after ultrasonic treatment to obtain the liposome solution loaded with the anticancer drug. The drug-carrying system of the invention has a lipophilic shell composed of phospholipid bilayers, and the inside of the drug-carrying system is a water core which can wrap hydrophobic or hydrophilic drugs; the potential changes with the change in the mole percentage of the fourth phospholipid; can prolong the blood circulation time of the medicine in vivo and improve the bioavailability of the medicine; in vivo, it is mainly distributed in liver and spleen.

Description

Medicine carrying system for carrying anti-cancer medicine and preparation method and application thereof
Technical Field
The invention relates to the technical field of nano medicaments, in particular to a medicament carrying system for carrying an anti-cancer medicament, and a preparation method and application thereof.
Background
Statistically, the incidence of neurodegenerative diseases, cancer, cardiovascular diseases and other related diseases is greatly increasing in recent years, and cancer has become the second leading cause of death worldwide, which poses a great threat to human life. To date, there are many cancer treatments, and conventional clinical treatments include surgical resection, drug therapy, radiotherapy, etc., and the intervention or treatment of tumor diseases by using chemical drugs is one of the more common methods. Single drug therapy indexes are narrow, requiring multiple administrations, often resulting in organ intolerance to drugs, and therefore, people focus on developing nanocarrier formulations. The nano carrier is a nano-scale conveying system, has extremely wide application, and plays a key role in the nano medical field of multi-mode imaging, drug delivery, targeted therapy and the like of human diseases. Compared with free drug molecules, the nano-carrier can improve the solubility of various drugs, reduce the toxic and side effects of the drugs, improve the treatment effect, reduce the administration times and the like. According to the difference of nano-carrier materials, the nano-carrier can be divided into a polymer nano-carrier, a lipid nano-carrier, a metal nano-carrier and an inorganic nano-carrier. These different types of nanocarriers have been widely used to study drug delivery at present.
In drug delivery systems, liposomes are structured as spherical vesicles with polar head groups facing the internal and external aqueous phases, typically less than 1000nm in diameter. Further, the bilayer may switch from an ordered state to a disordered state as the temperature increases. The phase transition temperature (Tm) at which this change occurs depends on the molecular structure of the lipid, thereby altering the permeability of the liposome and affecting the release of the drug. In addition, the liposome is considered to be one of the most widely used nanoparticles due to excellent biocompatibility and biodegradability, simple preparation method and capability of simultaneously coating hydrophilic and lipophilic molecules, so that the liposome also has unique characteristics. Currently, liposome formulations remain the main direction for the study of new pharmaceutical dosage forms, and liposomes can be generally divided into two categories: targeted liposomes and non-targeted liposomes. Targeted liposomes mostly achieve active accumulation in tissues and organs by surface modification with various ligands (e.g., antibodies, aptamers, proteins and peptides, etc.), while non-targeted liposomes allow passive accumulation in most tumor tissues mainly by enhancing the osmotic and retention Effects (EPR). Numerous documents have suggested that liposome formulations can be widely used to improve drug efficacy, reduce the toxicity of entrapped drugs, and improve tumor site specificity.
Disclosure of Invention
The invention aims to provide a drug-loading system for loading anticancer drugs, and a preparation method and application thereof. The prepared medicine carrying system has a lipophilic shell formed by phospholipid bilayers, and a water core is arranged inside the lipophilic shell and can wrap hydrophobic or hydrophilic medicines; the potential changes with the change in the mole percentage of the fourth phospholipid; can prolong the blood circulation time of the medicine in vivo and improve the bioavailability of the medicine; in vivo, it is mainly distributed in liver and spleen. Can be used for treating related diseases.
In order to solve the problems, the invention provides a preparation method of a drug-loading system for loading anticancer drugs, which comprises the following steps:
1) dissolving 1, 2-dioleoyl-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and an anticancer drug in dichloromethane, adding a fourth phospholipid, uniformly mixing, and performing rotary evaporation to remove an organic solvent to obtain a layer of phospholipid film; the fourth phospholipid is 1, 2-dioleoyl-sn-glycero-3-phosphate or 1, 2-dioleoyl-3- (dimethylamino) propane;
2) hydrating the phospholipid film with triple-distilled water, performing ultrasonic treatment for 5min, transferring the solution into a dialysis bag, and performing pure water dialysis for 12h under stirring to remove the unencapsulated anticancer drug, thereby obtaining the anticancer drug-loaded liposome solution.
Further, the molar ratio of the 1, 2-dioleoyl glycerol-3-phosphoethanolamine in the step 1) to the cholesterol, the 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and the fourth phospholipid is 69: 40: 4: x and X are 0, 12.6 or 48.4.
Further, the mass ratio of the anticancer drug to the total amount of the four phospholipids in the step 1) is 1: 4, the four phospholipids are 1, 2-dioleoyl glycerol-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and a fourth phospholipid;
further, the anti-cancer drug is adriamycin or docetaxel.
Further, the mass-to-volume ratio of the phospholipid membrane to the triple distilled water in the step 2) is 3.84 mg: 4 mL.
Further, the molecular weight cut-off of the dialysis bag in step 2) is 14000.
The invention also provides a medicine carrying system for carrying the anticancer medicine, which is prepared by the preparation method.
Furthermore, the hydration particle size of the medicine carrying system for loading the anticancer medicine is 90-160 nm.
The invention also provides application of the drug-loading system for loading the anticancer drug in preparation of a targeted liver and spleen anticancer drug.
Compared with the prior art, the invention has the following beneficial effects:
1. the drug carrier system of the invention can change the charging condition and the charge size of the surface charge of the particles by fixing the molar ratio of the three lipids in the components and changing the species and the molar ratio of the added fourth phospholipid, thereby improving the passive targeting capability of the drug carrier system in vivo.
2. The drug-loading system can prevent aggregation among particles, reduce the combination of the particles and plasma protein in vivo, prolong the blood circulation time of the drug and improve the bioavailability of the drug.
3. The drug carrier system can increase the biological distribution of the drug in vivo and target the liver and spleen.
4. The drug-carrying system of the invention has higher biocompatibility than other nano-carriers, biodegradability and low toxicity. In addition, the preparation is simple and convenient, the surface is easy to modify, and the rapid large-scale production can be realized.
Drawings
FIG. 1 is a drawing of the empty neutral Liposomes (0% Liposomes) provided in examples 1-1, the empty 10% anionic Liposomes and cationic Liposomes (10% DOPA/DODAP Liposomes) provided in examples 1-2, the empty 30% anionic Liposomes and cationic Liposomes (30% DOPA/DODAP Liposomes) provided in examples 1-3, the anticancer drug-loaded neutral Liposomes (0% Liposomes-DOX, 0% Liposomes-DTX) provided in examples 2-1 and 3-1, the anticancer drug-loaded 10% anionic Liposomes and cationic Liposomes (10% DOPA/DODODODOPOSOmes-DODAX, 10% DOPA/DODAP Liposomes-DTX) provided in examples 2-2 and 3-2, the anticancer drug-loaded 30% anionic Liposomes and cationic Liposomes (30% DOPA/DOPOMEX-DODAP), the examples 2-3, and 3-3, A hydrated particle size histogram of 30% DOPA/DODAP Liposomes-DTX), the empty 50% anionic and cationic Liposomes provided in comparative examples 1-1 (50% DOPA/DODAP Liposomes), the 50% anionic and cationic Liposomes loaded with anticancer drugs provided in comparative examples 1-2 and comparative examples 1-3 (50% DOPA/DODAP Liposomes-DOX, 50% DOPA/DODAP Liposomes-DTX); in FIG. 1, A is a graph showing the hydrated particle sizes of unloaded Liposomes and anticancer drug-loaded Liposomes measured after changing the mole percentage of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA), and B is a graph showing the hydrated particle sizes of unloaded Liposomes and anticancer drug-loaded Liposomes measured after changing the mole percentage of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP).
FIG. 2 is a drawing of the empty neutral Liposomes (0% Liposomes) provided in example 1-1, the empty 10% anionic and cationic Liposomes (10% DOPA/DODAP Liposomes) provided in example 1-2, the empty 30% anionic and cationic Liposomes (30% DOPA/DODAP Liposomes) provided in example 1-3, the anticancer drug-loaded neutral Liposomes (0% Liposomes-DOX, 0% Liposomes-DTX) provided in example 2-1 and example 3-1, the anticancer drug-loaded 10% anionic and cationic Liposomes (10% DOPA/DODODODOPOSOmes-DODAX, 10% DOPA/DODAP Liposomes-DTX) provided in example 2-2 and example 3-2, the anticancer drug-loaded 30% anionic and cationic Liposomes (30% DOPA/DOPOMEX-DODAP), the anticancer drug-loaded 30% anionic and cationic Liposomes (30% DOPA/DODAP-DODAP) provided in example 2-3, and example 3-3, A 30% DOPA/DODAP Liposomes-DTX), the potential variation statistical plots for the empty 50% anionic and cationic Liposomes provided in comparative examples 1-1 (50% DOPA/DODAP Liposomes), the 50% anionic and cationic Liposomes loaded with anticancer drugs provided in comparative examples 1-2 and comparative examples 1-3 (50% DOPA/DODAP Liposomes-DOX, 50% DOPA/DODAP Liposomes-DTX); in FIG. 1, A is a graph showing potential values of unloaded Liposomes and anticancer drug-loaded Liposomes measured after changing the mole percentage of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA), and B is a graph showing potential values of unloaded Liposomes and anticancer drug-loaded Liposomes measured after changing the mole percentage of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP).
FIG. 3 shows the anticancer drug-loaded neutral Liposomes (0% Liposomes-DOX, 0% Liposomes-DTX) provided in example 2-1 and example 3-1, the anticancer drug-loaded 10% anionic Liposomes and cationic Liposomes (10% DOPA/DODAP Liposomes-DOX, 10% DOPA/DODAP Liposomes-DTX) provided in example 2-2 and example 3-2, a statistical graph of the encapsulation efficiency of the anticancer drug-loaded 30% anionic and cationic Liposomes provided in examples 2-3 and 3-3 (30% DOPA/DODAP Liposomes-DOX, 30% DOPA/DODAP Liposomes-DTX), the anticancer drug-loaded 50% anionic Liposomes and cationic Liposomes provided in comparative examples 1-2 and 1-3 (50% DOPA/DODAP Liposomes-DOX, 50% DOPA/DODAP Liposomes-DTX); in fig. 3, a is a graph of the encapsulation efficiency of different mole percent liposomees loaded with Doxorubicin (DOX), and B is a graph of the encapsulation efficiency of different mole percent liposomees loaded with Docetaxel (DTX).
FIG. 4 is a transmission electron micrograph of unloaded neutral Liposomes (0% Liposomes) as provided in example 1-1.
Figure 5 is a docetaxel release profile under normoxic conditions for docetaxel, docetaxel-loaded neutral Liposomes provided in examples 3-1 (0% liposomees-DTX), docetaxel-loaded 50% anionic and cationic Liposomes provided in comparative examples 1-3 (50% DOPA/DODAP liposomees-DTX);
FIG. 6 shows the distribution of docetaxel, docetaxel-loaded neutral Liposomes (0% Liposomes-DTX) provided in example 3-1, docetaxel-loaded 10% anionic Liposomes and cationic Liposomes (10% DOPA/DODAP Liposomes-DTX) provided in example 3-2, docetaxel-loaded 30% anionic Liposomes and cationic Liposomes (30% DOPA/DODAP Liposomes-DTX) provided in example 3-3, docetaxel-loaded 50% anionic Liposomes and cationic Liposomes (50% DOPA/DODAP Liposomes-DTX) provided in comparative example 1-3 in vivo major organs; in fig. 6, panel a is the percent of drug per gram of tissue measured at 6h post-administration for various mole percent DOPALiposomes loaded with docetaxel, after removal of the heart, liver, spleen, lung and kidney; panel B is the percentage of drug per gram of tissue measured after removal of heart, liver, spleen, lung and kidney after 6h of administration for different mole percentages of DODAP lipomes loaded with docetaxel to total injected drug.
Figure 7 is the drug concentration in the blood of mice measured at different time points for docetaxel, docetaxel-loaded neutral Liposomes provided in example 3-1 (0% liposomees-DTX), docetaxel-loaded 50% anionic and cationic Liposomes provided in comparative examples 1-3 (50% DOPA/DODAP Liposomes-DTX).
Fig. 8 is a schematic structural diagram of a drug-loading system for loading anticancer drugs prepared by the present invention.
Detailed Description
For a further understanding of the invention, reference will now be made in detail to the preferred embodiments of the invention with reference to the following examples, but it is to be understood that the description is intended to illustrate further features and advantages of the invention, and not to limit the scope of the claims.
All of the starting materials of the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art.
Examples 1 to 1
Preparation of unloaded neutral liposomes:
dissolving 2.57mg (69 equivalents) 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.77mg (40 equivalents) Cholesterol (CHOL), 0.5mg (4 equivalents) 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) in dichloromethane; adding 0mg (0 equivalent) of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA) dissolved in dichloromethane, uniformly mixing the two, carrying out rotary evaporation for 5min to remove organic reagents to obtain a phospholipid film, hydrating the phospholipid film with 4ml of triple distilled water, carrying out ultrasonic treatment for 5min, transferring the solution to a dialysis bag (MW 14000), and carrying out pure water dialysis for 12h under stirring conditions to obtain an unloaded neutral liposome solution (0% Liposomes).
The particle size of the unloaded liposome solution is tested, and the result is shown in figure 1, and the particle size of the liposome is between 90-160 nm; as shown in FIG. 2, the liposome potential is near neutral, indicating successful construction of empty liposomes.
Putting the unloaded neutral liposome on a copper net, sucking redundant liquid by using filter paper, dyeing by using a 1% phosphotungstic acid solution, continuously washing for 3 times by using clear water after dyeing for 1-2 min, sucking redundant liquid by using the filter paper, observing the shape by using a transmission electron microscope (TEM, JEM-1230, Japan) after drying, and taking the transmission electron microscope picture of the unloaded neutral liposome solution (0% Liposomes) as shown in figure 4.
Examples 1 to 2
Preparation of unloaded 10% anionic and cationic liposomes:
(1) 2.22mg (69 equivalents) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.67mg (40 equivalents) of Cholesterol (CHOL), 0.43mg (4 equivalents) of 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in dichloromethane; 0.52mg (12.6 equivalents) of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA) dissolved in methylene chloride was added and the procedure was the same as in example 1-1 (except for transmission observation), to give an empty anionic liposome solution (10% DOPA Liposomes).
(2) 2.32mg (69 equivalents) 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.7mg (40 equivalents) Cholesterol (CHOL), 0.451mg (4 equivalents) 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in dichloromethane; 0.369mg (12.6 equivalents) of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP) dissolved in dichloromethane was added and the rest of the procedure was the same as in example 1-1 (except for transmission observation) to obtain an empty cationic liposome solution (10% DODAP Liposomes).
The particle size of the unloaded 10% anionic liposome and cationic liposome solution is tested, and the result is shown in figure 1, the particle size of the 10% anionic liposome and cationic liposome is between 90-160 nm; as shown in fig. 2, the potential of the 10% anionic liposome is negatively charged and the potential of the 10% cationic liposome is positively charged, indicating that the construction of the unloaded 10% anionic liposome and the cationic liposome was successful.
Examples 1 to 3
Preparation of empty 30% anionic and cationic liposomes:
(1) 2.22mg (69 equiv.) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.67mg (40 equiv.) of Cholesterol (CHOL), 0.43mg (4 equiv.) of 1, 2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol (DMG-PEG) are dissolved in dichloromethane; 0.52mg (12.6 equivalents) of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA) dissolved in methylene chloride was added and the procedure was the same as in example 1-1 (except for transmission observation), to give an empty anionic liposome solution (10% DOPA Liposomes).
(2) 2.32mg (69 equivalents) 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.7mg (40 equivalents) Cholesterol (CHOL), 0.451mg (4 equivalents) 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in dichloromethane; 0.369mg (12.6 equivalents) of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP) dissolved in dichloromethane was added and the rest of the procedure was the same as in example 1-1 (except for transmission observation) to obtain an empty cationic liposome solution (10% DODAP Liposomes).
The particle size of the unloaded 30% anionic liposome and cationic liposome solution is tested, and the result is shown in figure 1, the particle size of the 30% anionic liposome and cationic liposome is between 90-160 nm; as shown in fig. 2, the potential of the 30% anionic liposome is negatively charged and the potential of the 30% cationic liposome is positively charged, indicating that the construction of the empty 30% anionic liposome and the cationic liposome was successful.
Example 2-1
Preparation of doxorubicin-loaded neutral liposomes:
in example 1-1, 0.96mg of Doxorubicin (DOX) was added, and the procedure was otherwise the same as in example 1-1. The neutral liposome (0% Liposomes-DOX) loaded with adriamycin is obtained after dialysis.
The particle size of the doxorubicin-loaded neutral liposome solution is tested, and the result is shown in figure 1, and the particle size of the doxorubicin-loaded neutral liposome is between 90 and 160 nm; as shown in FIG. 2, the electric potential of the doxorubicin-loaded neutral liposome is neutral, which indicates that the doxorubicin-loaded neutral liposome is successfully constructed.
Examples 2 to 2
Preparation of adriamycin-loaded 10% anionic liposome and cationic liposome:
in steps (1) and (2) of example 1-2, 0.96mg of Doxorubicin (DOX) was added, respectively, and the rest of the steps were the same as in example 1-2. After dialysis, 10% anionic liposome and cationic liposome (10% DOPA Liposomes-DOX, 10% DODAP Liposomes-DOX) loaded with adriamycin are obtained.
The particle size of the adriamycin-loaded 10% anionic liposome and cationic liposome solution is obtained through testing, and the result is shown in figure 1, and the particle size of the adriamycin-loaded 10% anionic liposome and cationic liposome is between 90 and 160 nm; as shown in FIG. 2, the potential of the 10% anionic liposome loaded with adriamycin is negatively charged, and the potential of the 10% cationic liposome loaded with adriamycin is positively charged, which indicates that the 10% anionic liposome and the cationic liposome loaded with adriamycin are successfully constructed.
Examples 2 to 3
Preparation of doxorubicin-loaded 30% anionic liposomes and cationic liposomes:
in steps (1) and (2) of examples 1 to 3, 0.96mg of Doxorubicin (DOX) was added, respectively, and the rest of the steps were the same as in examples 1 to 3. After dialysis, 30% anionic liposome and cationic liposome (30% DOPA Liposomes-DOX, 30% DODAP Liposomes-DOX) loaded with adriamycin are obtained.
The particle size of the adriamycin-loaded solution of 30% anionic liposome and cationic liposome is obtained through testing, and the result is shown in figure 1, and the particle size of the adriamycin-loaded solution of 30% anionic liposome and cationic liposome is between 90 and 160 nm; as shown in FIG. 2, the potential of the doxorubicin-loaded 30% anionic liposome is negatively charged, and the potential of the doxorubicin-loaded 30% cationic liposome is positively charged, which indicates that the doxorubicin-loaded 30% anionic liposome and the cationic liposome are successfully constructed.
Example 3-1
Preparation of docetaxel-loaded neutral liposomes:
0.96mg of Docetaxel (DTX) was added to example 1-1, and the rest was the same as in example 1-1. Neutral liposome (0% lipomes-DTX) loaded with docetaxel is obtained after dialysis.
The structural schematic diagram of the neutral liposome loaded with docetaxel in this embodiment is shown in fig. 8, and it can be seen from fig. 8 that the neutral liposome has a lipophilic shell composed of phospholipid bilayers and an inner water core, and docetaxel is wrapped between the phospholipid bilayers.
The particle size of the neutral liposome solution loaded with docetaxel is obtained through testing, and the result is shown in figure 1, and the particle size of the neutral liposome loaded with docetaxel is between 90 and 160 nm; as shown in fig. 2, the potential of the docetaxel-loaded neutral liposome is neutral, which indicates that docetaxel-loaded neutral liposome is successfully constructed.
Examples 3 to 2
Preparation of docetaxel-loaded 10% anionic liposome and cationic liposome:
in example 1-2, 0.96mg of Docetaxel (DTX) was added in steps (1) and (2), respectively, and the rest of the procedure was the same as in example 1-2. After dialysis, docetaxel-loaded 10% anionic liposome and cationic liposome (10% DOPA Liposomes-DTX, 10% DODAP Liposomes-DTX) were obtained.
The particle size of the solution of the 10% anionic liposome and the cationic liposome loaded with the docetaxel is obtained through testing, and the result is shown in figure 1, and the particle size of the 10% anionic liposome and the cationic liposome loaded with the docetaxel is between 90 and 160 nm; as shown in fig. 2, the potential of the 10% anionic liposome loaded with docetaxel is negatively charged, and the potential of the 10% cationic liposome loaded with docetaxel is positively charged, which indicates that the construction of the 10% anionic liposome and the cationic liposome loaded with docetaxel is successful.
Examples 3 to 3
Preparation of docetaxel-loaded 30% anionic liposome and cationic liposome:
in examples 1-3, 0.96mg of Docetaxel (DTX) was added in steps (1) and (2), respectively, and the rest of the procedure was the same as in examples 1-3. After dialysis, 30% anionic liposome and cationic liposome (30% DOPA Liposomes-DTX, 30% DODAP Liposomes-DTX) loaded with docetaxel were obtained.
The particle size of the solution of 30% anionic liposome and cationic liposome loaded with docetaxel is tested, and the result is shown in figure 1, and the particle size of the solution of 30% anionic liposome and cationic liposome loaded with docetaxel is between 90 and 160 nm; as shown in fig. 2, the potential of the 30% anionic liposome loaded with docetaxel is negatively charged, and the potential of the 30% cationic liposome loaded with docetaxel is positively charged, which indicates that the construction of the 30% anionic liposome and the cationic liposome loaded with docetaxel is successful.
Comparative examples 1 to 1
Preparation of no-load 50% anionic liposome and cationic liposome:
(1) 1.07mg (69 equivalents) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.32mg (40 equivalents) of Cholesterol (CHOL), 0.21mg (4 equivalents) of 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in dichloromethane; 2.24mg (113 equivalents) of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA) dissolved in methylene chloride was added and the procedure was the same as in example 1-1 (except for transmission observation) to obtain an empty anionic liposome solution (50% DOPA Liposomes).
(2) 1.31mg (69 equivalents) 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.39mg (40 equivalents) Cholesterol (CHOL), 0.26mg (4 equivalents) 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in dichloromethane; 1.88mg (48.4 equivalents) of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP) dissolved in dichloromethane was added and the rest of the procedure was the same as in example 1-1 (except for transmission observation) to obtain an empty cationic liposome solution (50% DODAP Liposomes).
The particle size of the unloaded 50% anionic liposome and cationic liposome solution is tested, and the result is shown in figure 1, the particle size of the 50% anionic liposome and cationic liposome is between 90-160 nm; as shown in fig. 2, the potential of the 50% anionic liposome is negatively charged and the potential of the 50% cationic liposome is positively charged, indicating that the construction of the unloaded 50% anionic liposome and the cationic liposome was successful.
Comparative examples 1 to 2
Preparation of doxorubicin-loaded 50% anionic liposomes and cationic liposomes:
in comparative example 1-1, 0.96mg of Doxorubicin (DOX) was added in steps (1) and (2), respectively, and the remaining steps were the same as in comparative example 1-1. After dialysis, 50% anionic liposome and cationic liposome (50% DOPA Liposomes-DOX, 50% DODAP Liposomes-DOX) loaded with adriamycin are obtained.
The particle size of the adriamycin-loaded 50% anionic liposome and cationic liposome solution is obtained through testing, and the result is shown in figure 1, and the particle size of the adriamycin-loaded 50% anionic liposome and cationic liposome is between 90 and 160 nm; as shown in FIG. 2, the potential of the 50% anionic liposome loaded with adriamycin is negatively charged, and the potential of the 50% cationic liposome loaded with adriamycin is positively charged, which indicates that the 50% anionic liposome and the cationic liposome loaded with adriamycin are successfully constructed.
Comparative examples 1 to 3
Preparation of docetaxel-loaded 50% anionic liposome and cationic liposome:
in comparative example 1-1, 0.96mg of Docetaxel (DTX) was added in steps (1) and (2), respectively, and the remaining steps were the same as in comparative example 1-1. After dialysis, 50% anionic liposome and cationic liposome (50% DOPA Liposomes-DTX, 50% DODAP Liposomes-DTX) loaded with docetaxel were obtained.
The particle size of the solution of 50% anionic liposome and cationic liposome loaded with docetaxel is tested, and the result is shown in figure 1, and the particle size of the 50% anionic liposome and cationic liposome loaded with docetaxel is between 90 and 160 nm; as shown in fig. 2, the potential of the 50% anionic liposome carrying docetaxel is negatively charged, and the potential of the 50% cationic liposome carrying docetaxel is positively charged, which indicates that the 50% anionic liposome and cationic liposome carrying docetaxel are successfully constructed.
Example 4
DTX, 0% Liposomes-DTX, 50% DOPA Liposomes-DTX in vitro drug release profile under normoxic conditions:
docetaxel, the docetaxel-loaded liposome (0% lipomes-DTX) obtained in example 3-1 and the docetaxel-loaded liposome (50% DOPA lipomes-DTX) obtained in comparative example 1-3 are fully mixed, and then the mixture is stood, 0.2ml of supernatant is respectively taken when the time is 0h, 0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, and the same volume of fresh PBS solution is required to be supplemented while 0.2ml of supernatant is taken each time, so that the volume of the whole system is kept unchanged. Then, it was added to 3ml of methanol solution, and the content of DTX in the solution was detected by High Performance Liquid Chromatography (HPLC), thereby calculating the amount of cumulative release of DTX.
DTX release graph As shown in FIG. 5, it can be found from FIG. 5 that 0% Liposomes-DTX releases less drug at the same time compared with the other two groups, which illustrates that 0% Liposomes-DTX can prolong the release time of the drug and reduce the fluctuation of blood concentration.
Example 5
Distribution of DTX, different mole percent liposomes loaded with docetaxel in different organs:
ICR mice were randomly divided into 8 groups of 3 mice each, and each group was injected with free docetaxel caudal vein at a dose of 5mg/kg body weight, docetaxel-loaded Liposomes (0% lipomes-DTX) obtained in example 3-1, docetaxel-loaded 10% anionic Liposomes and cationic Liposomes (10% DOPA lipomes-DTX, 10% DODAP lipomes-DTX) obtained in example 3-2, docetaxel-loaded 30% anionic Liposomes and cationic Liposomes (30% DOPA lipomes-DTX, 30% DODAP lipomes-DTX) obtained in example 3-3, docetaxel-loaded 50% anionic Liposomes and cationic Liposomes (50% DOPA lipomes-dap, 50% DODAP lipomes-DTX) obtained in comparative example 1-3, respectively. After 6 hours of administration, chloral hydrate was injected into the abdominal cavity to anesthetize the mice, and then the tissues of the heart, liver, spleen, lung, kidney, etc. were separately removed by perfusion with physiological saline. The tissue was weighed and homogenized using a homogenizer. Adding 5ml of mixed solution (chloroform: methanol is 4:1) into the homogenized tissue, crushing, performing ultrasonic treatment for 10min, centrifuging for 10min at 8000r/min, taking out the lower layer of chloroform solution, performing spin drying, adding 3ml of methanol solution for redissolution, centrifuging for 10min at 8000r/min, measuring the content of the drug in different tissues in the supernatant by using HPLC, wherein the statistics of the percentage of the drug in the body tissue in each gram of tissue in the total injected drug is shown in FIG. 6.
As can be seen from FIG. 6, Liposomes are mainly distributed in the liver and spleen, and the highest drug content was shown in the liver and spleen at a DOPA or DODAP molar ratio of 30%.
Example 6
DTX, 0% Liposomes-DTX, 50% DOPA Liposomes-DTX pharmacokinetics:
healthy BALB/c mice were randomly divided into 3 groups of 3 mice each, and each group was treated with 5mg/kg body weight of docetaxel by tail vein injection (control group 1), docetaxel-loaded neutral Liposomes obtained in example 3-1 (0% Liposomes-DTX), docetaxel-loaded 50% anionic Liposomes obtained in comparative examples 1-3 (50% DOPA Liposomes-DTX, control group 2). Collecting blood from orbit at 0.05h, 0.5h, 1h, 2h, 4h, 6h, 12h, and 24h after tail vein administration to obtain 1ml blood, standing at 4 deg.C, centrifuging at 3000r/min for 5min, and collecting 0.2ml upper layer serum. Adding the extract into 0.2ml PBS solution and 3ml chloroform solution, vortexing for 5min, centrifuging at 5500r/min for 10min, taking out chloroform layer liquid, adding 2ml methanol for redissolving after the chloroform is spun off, centrifuging at 8000r/min for 10min, and measuring the drug content in different tissues in the supernatant by using HPLC.
According to fig. 7, the DTX concentration-time profiles in the plasma were measured at different time points within 24h of the administration of ICR mice. Compared with the control group 1-2, the 0% Liposomes-DTX has long half-life period in vivo and slow clearance rate, can prolong the blood circulation time of the drug in vivo and simultaneously improve the bioavailability of the drug in vivo.
Fluorescence spectrophotometer and HPLC measurements of the anticancer drug-loaded neutral Liposomes (0% Liposomes-DOX, 0% Liposomes-DTX) provided in example 2-1 and example 3-1, the anticancer drug-loaded 10% anionic and cationic Liposomes (10% DOPA/DODAP Liposomes-DOX, 10% DOPA/DODAP Liposomes-DTX) provided in example 2-2 and example 3-2, the anticancer drug-loaded 30% anionic and cationic Liposomes (30% DOPA/DODAP Liposomes-DOX, 30% DOPA/DODAP Liposomes-DTX) provided in example 2-3 and example 3-3, the anticancer drug-loaded 50% anionic and cationic Liposomes (50% DOPA/DODAP Liposomes-DOX, 30% DOPA/DODAP Liposomes-DTX) provided in comparative examples 1-2 and comparative examples 1-3, 50% DOPA/DODAP Liposomes-DTX), a statistical graph of the encapsulation efficiency is shown in FIG. 3.
As can be seen from FIG. 3, the encapsulation efficiency of DTX-loaded liposomes is higher than that of DOX-loaded liposomes, which indicates that the DTX-loaded liposomes z can reduce the administration frequency during the treatment process, thereby reducing the drug resistance of tissues or cells.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (9)

1. The preparation method of the anticancer drug loaded system is characterized in that the anticancer drug loaded system is a liposome solution loaded with anticancer drugs, and the preparation method comprises the following steps:
1) dissolving 1, 2-dioleoyl-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and an anticancer drug in dichloromethane, adding a fourth phospholipid, uniformly mixing, and performing rotary evaporation to remove an organic solvent to obtain a layer of phospholipid film; the fourth phospholipid is 1, 2-dioleoyl-sn-glycero-3-phosphate or 1, 2-dioleoyl-3- (dimethylamino) propane;
2) hydrating the phospholipid film with triple-distilled water, performing ultrasonic treatment for 5min, transferring the solution into a dialysis bag, and performing pure water dialysis for 12h under stirring to remove the unencapsulated anticancer drug, thereby obtaining the anticancer drug-loaded liposome solution.
2. The method according to claim 1, wherein the molar ratio of 1, 2-dioleoyl glycerol-3-phosphoethanolamine to cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol, and the fourth phospholipid in step 1) is 69: 40: 4: x and X are 0, 12.6 or 48.4.
3. The method according to claim 1, wherein the mass ratio of the anticancer drug to the total amount of the four phospholipids in step 1) is 1: 4, the four phospholipids are 1, 2-dioleoyl glycerol-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and a fourth phospholipid.
4. The preparation method of claim 1, wherein the anticancer drug is doxorubicin or docetaxel.
5. The method according to claim 1, wherein the mass-to-volume ratio of the phospholipid membrane to the triple distilled water in step 2) is 3.84 mg: 4 mL.
6. The method of claim 1, wherein the dialysis bag in step 2) has a molecular weight cut-off of 14000.
7. The drug-carrying system for carrying the anticancer drug prepared by the preparation method of any one of claims 1 to 6.
8. The anticancer drug-loaded drug delivery system of claim 7, wherein the hydrated particle size of the anticancer drug-loaded drug delivery system is 90-160 nm.
9. The use of the anticancer drug loaded drug delivery system of claim 8 in the preparation of a targeted liver and spleen anticancer drug.
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